Throughout this application various publications are referred to in parenthesis. Full citations for these references may be found at the end of the specification immediately preceding the claims. The disclosures of these publications are hereby incorporated by reference in their entireties into the subject application to more fully describe the art to which the subject application pertains.
The epidermal growth factor receptor (EGFR) is a transmembrane protein expressed in all epithelial surfaces. It plays an important physiological role in epithelial repair and regeneration. Epidermal growth factor (EGF) is a peptide secreted by salivary glands and other glands associated with epithelial surfaces that binds to a specific area in the extracellular domain of EGFR. Upon binding it generates a signal that is transmitted inside the cell. The first intracellular event as a result of EGF binding is a conformational change of the intracellular domain of EGFR that allows adenosine 5′-triphosphate (ATP) to enter the so-called tyrosine kinase (TK) domain, a pocket that contains a tyrosine residue, and donate a phosphate group to the tyrosine residue. The intracellular EGFR carrying a phosphorylated tyrosine becomes capable of associating with other intracellular proteins and originates a series of biochemical reactions that propagate downstream through a very complex network. The best known arms of this network are the mitogen-activated protein kinase (MAPK) pathway, which results in tumor cell division upon activation, and the AKT pathway, which results in enhanced cell survival upon activation. The results of EGFR activation are therefore increased cell proliferation and enhanced cellular tolerance to different insults.
Many tumors overexpress EGFR compared to vicinal normal tissues or the epithelial surface from which they originate or have a mutated version of EGFR, intrinsically activated or with an enhanced susceptibility to activation. Such overexpression is thought to be one of the many mechanisms by which tumor cells gain a growth advantage, a key characteristic of the malignant phenotype. Consequently, blocking the EGFR signaling pathway is thought to be a rational strategy for the treatment of many human malignancies. There are basically two ways to inhibit upstream the EGFR signaling pathway: 1) preventing EGF and other natural peptide ligands from binding to the extracellular EGFR domain by the use of specific monoclonal antibodies, and 2) preventing ATP and other phosphate donors from entering the TK pocket of the intracellular EGFR domain by the use of small molecules that structurally fit very well into the pocket (the so-called EGFR TK inhibitors).
After years of discovery efforts and clinical evaluation, EGFR inhibitors have been recently shown to be active antitumor agents against a variety of solid tumors including but not limited to colorectal carcinoma, non-small cell lung cancer, head and neck cancer and malignant gliomas (Conen et al., 2003; Lage et al., 2003; Lorusso, 2003; Vanhoefer et al., 2004). Clinical benefit defined as relief of symptoms or prolongation of survival has been so far demonstrated with the anti-EGFR antibody cetuximab (Erbitux®) and the EGFR tyrosine kinase (TK) inhibitors gefitinib (Iressa®) and erlotinib (Tarceva®). Many additional agents belonging to this class are being developed. As of today, FDA approved indications include chemorefractory colorectal carcinoma and non-small cell lung cancer, head and neck carcinoma, and pancreatic carcinoma. Many clinical studies using these agents alone or in combination, for refractory or chemo naive patients with a variety of other malignant diseases are in progress. It is anticipated that as many as 200,000 patients in the USA may receive these agents every year in the near future.
Although these agents do not cause life threatening toxicities, the major side effect is a skin rash that occurs in 60-70% of patients, affects mostly face and trunk, and causes discomfort and unfavorable cosmetic changes in many cases. Main symptoms caused by the skin rash are itching, dryness, and secondary infection. The occurrence and intensity of the rash are clearly dose-related and the median time of occurrence is 10 days after initiation of therapy. About 10% of patients discontinue therapy due to skin toxicity.
Most clinical studies have shown that most patients who develop skin rash as a result of anti-EGFR therapy tend to live longer. It is thought that the occurrence of skin rash requires both effective EGFR inhibition in the skin and a competent immune system that is able to respond to the tissular insult caused by such inhibition with an appropriate inflammatory response. As there is growing evidence that the skin rash is a surrogate indicator of antitumor efficacy and clinical benefit (Cohen et al., 2003), increasing dosing of anti-EGFR agents to cause a skin rash may become a common practice. If that is the case, treatment of the skin rash will also become of increasing importance. As a result, treatment of the skin rash is also becoming of increasing importance. There are no rational, scientifically proven and clinically effective methods available for the treatment of this form of skin rash. Topical or systemic antibiotics, anti-inflammatory agents, retinoids, topical lubricants, and other types of remedies have been tried in an empirical fashion with poor or inconsistent results. As of today there is no established therapy or prevention for this new skin disease, a condition that is expected to affect about 150,000 individuals in the USA every year in the very near future.
Vitamin K has been used for treatment of blood vessel disorders of the skin, cosmetic skin treatment, and skin treatment following laser treatment (U.S. Pat. No. 5,510,391; U.S. Patent Application Publication No. US 2003/0170187; PCT International Publication Nos. WO 97/39746, WO 02/13780, WO 03/101415, WO 2004/019923; Lou et al., 1999; Shah et al., 2002). However, topical administration of vitamin K3 can cause dermatitis (Page et al., 1942) and vesiculation of the skin (Ulbrich, 1961).